Regression of Intracranial Meningiomas Following Treatment with Cabozantinib

Case Report Regression of Intracranial Meningiomas Following Treatment with Cabozantinib

Rupesh Kotecha 1,2,*, Raees Tonse 1, Haley Appel 1, Yazmin Odia 2,3 , Ritesh R. Kotecha 4 , Guilherme Rabinowits 2,5 and Minesh P. Mehta 1,2

1 Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA; [email protected] (R.T.); [email protected] (H.A.); [email protected] (M.P.M.) 2 Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; [email protected] (Y.O.); [email protected] (G.R.) 3 Department of Neuro Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA 4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; [email protected] 5 Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA * Correspondence: [email protected]; Tel.: +1-(786)-527-8140

Abstract: Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding signiﬁcant responses in two radiographically diagnosed intracranial meningiomas in a patient with

concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the

Citation: Kotecha, R.; Tonse, R.; role of VEGF agents as experimental therapeutics in meningioma and the current understanding of Appel, H.; Odia, Y.; Kotecha, R.R.; the biological pathways underlying meningioma growth, this may represent a new oral therapeutic Rabinowits, G.; Mehta, M.P. alternative, warranting prospective evaluation. Regression of Intracranial Meningiomas Following Treatment Keywords: meningioma; cabozantinib; VEGF; targeted therapy with Cabozantinib. Curr. Oncol. 2021, 28, 1537–1543. https://doi.org/ 10.3390/curroncol28020145 1. Introduction Received: 24 March 2021 Meningiomas account for approximately one-third of primary central nervous system Accepted: 15 April 2021 Published: 18 April 2021 tumors in adults. Although most meningiomas are well-differentiated, with low prolifera- tive capacity [1], recent analyses using the updated grading criteria adopted by the World Health Organization (WHO) have demonstrated that as many as 15% to 20% should be Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in classified as atypical WHO Grade II [2]. In the Radiation Therapy Oncology Group (RTOG) published maps and institutional affil- 0539, a phase II cooperative group trial assessing the safety and efficacy of risk-adapted iations. meningioma treatment strategies, “high-risk” meningioma patients (WHO grade II subto- tal resection, recurrent grade II, or any grade III), experienced a 3-year progression-free survival (PFS) of only 59%, with a 3-year local control rate of only 69% [3], prompting broad agreement for the need for more effective multimodality therapy, and the optimization of treatment strategies in this patient population. Copyright: © 2021 by the authors. Evaluation of systemic therapies in recurrent and higher grade meningiomas suggest Licensee MDPI, Basel, Switzerland. This article is an open access article that most chemotherapeutic agents have minimal to no activity against this disease group. distributed under the terms and Agents such as hydroxyurea, dacarbazine, ifosfamide, temozolomide, irinotecan, and α- conditions of the Creative Commons interferon have demonstrated no clinical efficacy [4]. The pathogenesis of meningioma is Attribution (CC BY) license (https:// incompletely understood, and studies have now focused on gene expression profiling and creativecommons.org/licenses/by/ DNA methylation arrays to characterize transcriptional and epigenetic changes in the hope 4.0/). of identifying prognostic markers and molecular drivers. Emerging data have identified

Curr. Oncol. 2021, 28, 1537–1543. https://doi.org/10.3390/curroncol28020145 https://www.mdpi.com/journal/curroncol Curr. Oncol. 2021, 28 1538

the upregulation of pathways involved in growth, proliferation, and angiogenesis, including EGFR, mTOR, PDGF, and VEGF, suggesting these as potential actionable targets [5]. Moreover, high MET expression has been demonstrated to be a predictor for recurrence in meningioma [6]. Markers of angiogenesis, including increased vessel density and VEGF expression, are detectable in meningiomas, and have been linked with grade and prognosis [7,8]. At least two VEGF targeting agents have previously been tested in this setting: bevacizumab and sunitinib. Bevacizumab showed evidence of antitumor activity, including radiographic responses and prolonged PFS in a retrospective series [9]. A prospective, multi-center single-arm phase II trial investigated the efficacy of sunitinib, a small molecule tyrosine kinase inhibitor (TKI), against VEGFR and PDGFR in 36 patients with WHO grade II and III recurrent or progressive meningiomas, resulting in a very modest median PFS of 5.2 months [10]. Reports focused on recurrent WHO grade I meningiomas are limited. A phase II study evaluated the combination of bevacizumab and everolimus, an mTOR inhibitor, in patients with recurrent or progressive meningioma (n = 5 WHO grade I, 17 total) [11]. Interestingly, the median PFS was greater for WHO grade II and III tumors (22 months) as compared to grade I tumors (17 months). Similarly, another phase II study investigated the efficacy of Vatalanib, a small molecule protein kinase inhibitor with activity against VEGF receptors, PDGFR-beta, and c-kit in refractory meningiomas (n = 2 WHO grade I, 25 total), with overall modest activity [12]. Together, these studies demonstrate the promise of VEGF inhibitors in meningioma. Cabozantinib is a multitarget oral TKI with potent activity against MET and VEGF receptor 2 (VEGFR2) [13]. It is FDA-approved for the treatment of progressive metastatic medullary thyroid cancer and advanced renal cell carcinoma. In this case study, we report a patient with metastatic thyroid cancer treated with cabozantinib who demonstrated a marked response in two previously untreated, incidental intracranial meningiomas. To the best of our knowledge and based on a search of the medical literature (MEDLINE, accessed on 29 February 2020), this represents the first documented case of a response to this oral agent in meningioma and provides an encouraging example for further study.

2. Case Report A 65-year-old male with a past medical history significant for medically controlled hypertension presented initially with dysphonia and was found to have a large thyroid mass displacing the trachea and extending into the superior mediastinum. He underwent a total thyroidectomy; pathology revealed follicular thyroid carcinoma, insular variant, and he was treated with 200 mCi of oral radioactive iodine (RAI). A seven-day post-iodine scan revealed evidence of significant residual iodine-avid tissue within the thyroid bed, as well as multiple non-calcified pulmonary nodules with increased iodine uptake suspicious for bilateral metastatic pulmonary disease. He later developed symptomatic local recurrence, as well as an increase in the burden of distant metastatic disease, approximately 1 year after resection, and 9 months after RAI. He was treated with Lenvatinib 20 mg PO once daily. After a few weeks, he continued to have persistent symptoms of vocal cord paralysis and, given concern for persistent disease, underwent total laryngopharyngectomy, cervical esophagectomy, and post-operative external beam radiotherapy, and his systemic therapy was discontinued. MRIs of the spine at that time revealed a T12 metastasis with an epidural tumor treated with stereotactic body radiotherapy. At age 70, five years after initial presentation, he presented with headaches, and an MRI scan of the brain revealed a left posterior frontal parafalcine lesion measuring 2 × 1.5 × 2.5 cm, along with two stable intraventricular meningiomas (measuring approximately 8.5 and 9.2 mm each). Interval brain MRI performed 2.5 months later, at the time of transfer to our center, revealed that the left parafalcine mass had increased in size to 3.5 × 3.4 × 2.4 cm, with moderate mass effect on the motor strip, with the two intraventricular putative meningiomas stable in size. Given the patient’s progressive weakness and lesion size, he underwent resection of the left posterior frontal parafalcine mass, and Curr. Oncol. 2021, 28, 3

2.4 cm, with moderate mass effect on the motor strip, with the two intraventricular putative meningiomas stable in size. Given the patient’s progressive weakness and lesion size, Curr. Oncol. 2021, 28 1539 he underwent resection of the left posterior frontal parafalcine mass, and pathology con- firmed metastatic thyroid carcinoma consistent with his known primary. He underwent post-operative stereotactic radiosurgery to the surgical cavity and continued observation waspathology recommended conﬁrmed for metastaticthe putative thyroid stable carcinoma meningiomas. consistent Subsequent with his restaging known primary. studies re- He underwent post-operative stereotactic radiosurgery to the surgical cavity and contin- vealed progressive metastatic cancer, with an increase in the size and number of meta- ued observation was recommended for the putative stable meningiomas. Subsequent staticrestaging pulmonary studies nodules, revealed nodal progressive progression metastatic in the cancer, neck, with and an enlarging increase in osseous the size andmetasta- ses.number His two-month of metastatic post-treatment pulmonary nodules, brain MRI nodal revealed progression no evidence in the neck, of andprogression enlarging of the diseaseosseous within metastases. the surgical His two-month cavity and post-treatment the continued brain stability MRI revealed of the two no evidenceintraventricular of meningiomas.progression ofHe the was disease started within on systemic the surgical therapy cavity with and thecabozantinib continued stability60 mg PO of daily the for histwo metastatic intraventricular thyroid meningiomas. cancer, which He was was starteddose-reduced on systemic 6 weeks therapy later with to cabozantinib 40 mg PO daily due60 to mg modest PO daily fatigue. for his metastaticInterval follow-up thyroid cancer, brain which MRI wasperformed dose-reduced 8 weeks 6 weeks following later to treat- ment40 mgof POthe dailybrain due metastasis to modest fatigue.and 6 weeks Interval post-cabozantinib follow-up brain MRI demonstrated performed 8 weeks no radio- following treatment of the brain metastasis and 6 weeks post-cabozantinib demonstrated graphic recurrence at the surgical bed, but an unexpected and dramatic reduction in size no radiographic recurrence at the surgical bed, but an unexpected and dramatic reduction andin volume size and volumeof the intracranial of the intracranial meningiomas meningiomas (60% (60% and and 40% 40% volumetric volumetric reduction) reduction) (see Figure(see Figure1). This1). response This response was sustained was sustained at an at interval an interval brain brain MRI MRI performed performed for for the the surveil- lancesurveillance of brain metastasis of brain metastasis approximately approximately 3 months 3 months on cabozantinib on cabozantinib and andcontinued continued until his mostuntil recent his most follow-up recent follow-up MRI performed MRI performed approximately approximately 1 year 1 yearafter after starting starting therapy. therapy.

FigureFigure 1. (A 1.) Sequential(A) Sequential MR MR images images demonstrating demonstrating the the changes changes inin size size and and volume volume of theof the right right putative putative intraventricular intraventricular meningiomameningioma before before and and after after treatment treatment with with cabozantinib. cabozantinib. (B)) SequentialSequential MR MR images images demonstrating demonstrating the changesthe changes in size in size and volumeand volume of the of left the leftputative putative intraventricular intraventricular meningioma meningioma beforebefore and and after after treatment treatment with with cabozantinib. cabozantinib.

3. Discussion3. Discussion Herein,Herein, we we describe describe a a significant significant and and unexpected unexpected early early intracranial intracranial response response to two to two intracranialintracranial meningiomas meningiomas in in a patient treated treated with with cabozantinib. cabozantinib. This This response response remains remains in in line with prospective evidence demonstrating activity of VEGF directed therapies in menin- line with prospective evidence demonstrating activity of VEGF directed therapies in men- giomas, but represents the first report, to our knowledge, using the potent VEGFR TKI ingiomas,cabozantinib. but represents Given the currentthe first understanding report, to our of knowledge, the biological using mechanisms the potent underlying VEGFR TKI cabozantinib.meningioma Given growth, the the current tolerability understanding of the agent, andof the the biological ease of oral mechanisms administration, underlying this meningiomacase example growth, provides the rationale tolerability for prospective of the agent, investigation and the ease of disease-specific of oral administration, activity. this case exampleSeveral provides studies and rationale reports havefor prospectiv detailed thee investigation activity of VEGF of directeddisease-specific therapies activity. for patientsSeveral with studies meningiomas, and reports especially have detailed for those the with activity high-grade/recurrent of VEGF directed disease. therapies Due for patientsto the differenceswith meningiomas, in doses used especially across thefor studies,those with as well high-grade/recurrent as the duration of treatment, disease. Due to theheterogeneity differences of patientin doses selection, used across variation the in studies, prior radiotherapy, as well as the the potential duration for of diagnos- treatment, tic uncertainty in radiation necrosis vs. true tumor progression, and the lack of long-term prospective follow-up, the data remain inconclusive (See Table1). Curr. Oncol. 2021, 28 1540

Table 1. Selected clinical studies evaluating the use of VEGF agents in meningioma patients.

Author and Studied Mechanism of Number of Prior WHO Grade Study Type Prior RT * PFS 6 ** Year Drug Action Patients Surgery Inclusion Puchner et al., Anti-VEGF Bevacizumab Case report 1 1 1 III NA 2010 [14] antibody Goutagny Anti-VEGF Bevacizumab Case report 1 NA NA NA NA et al., 2011 [15] antibody Lou et al., Anti-VEGF Bevacizumab Retrospective 14 14 11 I,II,III 86% 2012 [16] antibody Nayak et al., Anti-VEGF Bevacizumab Retrospective 15 15 15 II,III 44% 2012 [17] antibody Nunes et al., Anti-VEGF Bevacizumab Retrospective 15 NA NA NA 93% 2013 [18] antibody Hawasli et al., Bevacizumab, Anti-VEGF Retrospective 10 9 5 NA NA 2013 [19] Pazopanib antibody, TKI Raizer et al., VEGFR + Vatalanib Phase II 17 16 12 I,II,III 60% 2014 [12] PDGFR TKI Alanin et al., Anti-VEGF Bevacizumab Retrospective 7 NA NA NA NA 2015 [20] antibody Kaley et al., VEGFR + Sunitinib Phase II 36 36 35 II,III 42% 2015 [10] PDGFR TKI Furtner et al., Anti-VEGF Bevacizumab Retrospective 5 NA NA II,III NA 2015 [21] antibody Grimm et al., Anti-VEGF Bevacizumab Phase II 40 40 40 I,II,III 27% 2015 [22] antibody Shih et al., 2016 Bevacizumab, Anti-VEGF Phase II 17 16 12 I,II,III 69% [11] Everolimus antibody * RT = radiotherapy; ** 6-month progression-free survival.

Sunitinib demonstrated promising activity in a phase II meningioma trial [10]; however, in untreated renal cell carcinoma brain metastasis, the objective response rate was 0% [23]. There are currently only three ongoing phase II prospective trials for patients with sporadic recurrent or progressive meningioma: one using bevacizumab monotherapy (NCT01125046), another studying a combination of bevacizumab and electric field therapy (NCT02847559), and a third evaluating the activity of a single agent PD-1 inhibitor Pembrolizumab (NCT03279692) (see Supplemental Table S1). Cabozantinib is a small molecule inhibitor of multiple tyrosine kinases including MET, VEGFR2, RET, and AXL. Selective inhibition of VEGFR2 may lead to increased invasiveness and metastasis, and preclinical models suggest that the inhibition of VEGFR2, together with c-MET, may decrease tumor size and invasiveness [24]. Cabozantinib was FDA approved in 2012 for patients with progressive metastatic medullary thyroid cancer based on improved PFS compared to placebo (11.2 months vs. 4.0 months, p < 0.001) [25]. In 2016, cabozantinib was approved for adults with advanced renal cell carcinoma following prior antiangiogenic therapy and, subsequently, in the first-line setting [26]. There has also been documented experience of treatment of primary intracranial tumors with cabozantinib. A phase II trial examined the efficacy and safety of cabozantinib in 222 patients with progressive or recurrent GBM, and initial results demonstrated modest clinical activity in patients who had received prior antiangiogenic therapy [27]. More promising activity was observed in a subsequent subset of 152 patients not previously treated with antiangiogenic therapy (ORR of 15% for the combined dosing cohorts and a median PFS of 3.7 months in both cohorts) (see Supplemental Table S2) [28]. Therefore, this agent likely has intracranial penetration (not a requirement for meningioma) based on the limited efficacy in recurrent GBM. Several limitations are to be noted from this case example. First, the lack of histopatho- logical evaluation of the intraventricular lesions prevents a definitive diagnosis from being made and precludes biomarker evaluation. However, this was not clinically indicated in Curr. Oncol. 2021, 28 1541

this patient, as the intraventricular lesions were present and stable during the patient’s cancer course and responded to the systemic therapy (unexpectedly); therefore, pathological evaluation has not been necessary. We do consider these lesions to be meningiomas versus brain metastasis for the following reasons: (1) the development of the single brain metastasis and its progression in size while treatment was arranged in the setting of the intraventricular lesions remaining stable during interval imaging; (2) the rarity of intraventricular brain metastases, representing only 1–5% of cases in general [29] and only a single case report of an intraventricular thyroid cancer metastasis reported in the literature [30]; (3) radiographic and biopsy-proven extracranial disease progression now over 1 year from the initiation of cabozantinib, along with intracranial disease progression with development of additional intracranial lesions, but continued response and stability of the intraventricular lesions, which would be strikingly discordant. An additional limitation to note is that this particular patient was presumed to have low-grade meningiomas based on their lack of growth trajectory and imaging appearance and responded to single agent Cabozantinib. Therefore, although similar VEGFR-directed agents have been utilized in those with higher grade recurrent or progressive disease, the responses may differ across different grades of meningioma, and the evaluation of the molecular underpinnings are key to better understanding the response assessments. Additionally, the development of non-invasive or liquid biomarkers are equally im- portant, especially if pathological evaluation is unable to be performed, such as in this particular case. Recently, non-invasive techniques, such as liquid biopsy or CSF analysis, have emerged as viable options in this space [31,32]. Circulating microRNAs (miRNAs) and DNA methylation hold great promise as novel clinical blood-based biomarkers for meningioma diagnosis and prognosis [33,34]. Currently, many more biomarkers are being identiﬁed, and research on the effectiveness of these techniques is being performed to determine their usefulness for the detection and monitoring of genomic alterations [31]. Additionally, we also considered, in this case, whether the radiographic response was primarily due to vasculature changes as a result of the targeted therapy or a direct effect on the meningioma cells, as it is known that meningiomas do not show an angiogenic switch involving VEGF, as is the case with gliomas. Nevertheless, the biological activity of VEGF and the molecular underpinnings behind meningioma proliferation suggest that it is a potential target for antiangiogenic therapy in meningiomas of all WHO grades.

4. Conclusions Meningiomas are common tumors in a neuro-oncology practice, but there are few systemic options for patients with recurrent disease. Clinical experience with VEGF inhibitors demonstrates modest results. This case of a patient treated with the oral agent cabozantinib, with potent activity against MET and VEGFR2, may represent a new therapeutic option in this patient population with a highly unmet need. Unfortunately, we did not have actual tumor tissue from any of the lesions, as resection was not clinically indicated and therefore correlating the response with biomarker expression is not possible. Moreover, these lesions were stable over multiple MRIs, and radiographically most consistent with meningioma, unlike the known and resected thyroid metastatic lesion in the brain. Given the preclinical understanding of the molecular underpinnings of meningioma and the lack of effective systemic therapeutic options, a prospective evaluation of Cabozantinib is encouraged and warranted in patients with relapsed or refractory disease. This study is currently in development with the objectives of evaluating the PFS, overall response rate, overall survival, safety and tolerability, and quality of life for patients treated for recurrent meningioma of WHO Grades I–III. Correlation of MET expression, angiogenesis receptor status, and inﬂammatory signatures by gene expression proﬁling with response to cabozantinib on pre-treatment tissue samples will lead to a better understanding of this potential therapeutic modality. Similar initiatives are encouraged in this space to help provide alternatives for this challenging disease. Curr. Oncol. 2021, 28 1542

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/curroncol28020145/s1. Table S1. Ongoing trials of VEGF agents in meningioma patients; Table S2. Select clinical studies evaluating Cabozantinib in patients with primary or metastatic CNS tumors. Author Contributions: R.K., R.T., and H.A.: drafting the manuscript; R.K., R.T., and R.R.K.: analysis or interpretation of data. Y.O., G.R., and M.P.M.: critically revised and gave final approval for publication of the paper. All authors have read and agreed to the published version of the manuscript. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Written informed consent was obtained from the patient for the publication of this case report. Data Availability Statement: Not applicable. Conflicts of Interest: R.K.: Honorarium from Elsevier, Elekta AB, Accuray Inc., Novocure Inc. Research support from Novocure Inc. and Medtronic Inc. R.T.: None. H.A.: None. Y.O.: Advisory Board for Novocure Inc. and Abbvie Inc. Research support from Novocure Inc. and BMS. R.R.K.: None. G.R.: Scientific Advisory Board/Consultant (Merck, Regeneron, Sanofi Genzyme, Pfizer, EMD Serono, Castle); Shares (Syros and Regeneron pharmaceuticals). M.P.M.: Consulting for Karyopharm, Tocagen, AstraZeneca, Blue Earth Diagnostics, Celgene, Abbvie. Board of Directors: Oncoceutics.

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